Integrin Activation as a Treatment for Leukocyte Adhesion Deficiencies

Leukocyte adhesion deficiency type ILADis a rare and often fatal primary immunodeficiencyIt is caused by autosomal recessive mutations in the gene ITGBwhich encodes CDthe commonsubunitof thefamily of integrin cell adhesion molecules that are specifically expressed on cells of hematopoietic origin like leukocytesAs a result of decreased function ofintegrinsleukocytes cannot extravasate from the vasculature and patients suffer from severe life threatening and recurrent non pustular infections of the soft tissue including skinmucosal membranesand intestinal trackHematopoietic stem cell transplantation is curativebut it is not without significant riskIn more moderate forms of the diseaseintegrinexpression is characterized as being betweenof normal levelsAn intriguing approach to overcoming the adhesion defects found in moderate LADpatients would be to directly activateintegrinslikeLso that even low levels of this integrin would be sufficient to support essential leukocyte functionsScientists at the Texas Heart Institute have developed a library of small molecule compounds that can directly bind and activate integrin cell adhesion receptors including the integrinLThese compounds are currently licensed toHills Pharma and are being developed for immuno oncologyIOindications as they can stimulate the immune system and synergize with checkpoint blockade therapies like anti CTLAand anti PD LHoweverthere is a clear opportunity to leverage these compounds as a treatment strategy to activate integrins likeLand directly target the cause of LADIn this phase I SBIR proposalwe will test the hypothesis that activation ofintegrins with small molecule compounds can overcome the adhesion defects seen in leukocytes of LADpatientsand in an animal model of moderate LADIn proposed aims we will screen overintegrin activating compoundsfromstructural classesto identify potentintegrin activatorsRepresentative compounds from each structural class will then be tested against a panel of mutations identified from moderate LADpatientsIn vivo proof of concept experiments will be performed by testing integrin activating compounds in acute inflammatory responses in the CDhypo mousewhich mimics moderate LADLastlypharmacodynamic models of compound activity will be developed to inform future clinical developmentThe goal of this drug development program is the development of a safe and effective orally available treatment for patients with moderate to severe LADan orphan disease indication for which there are no effective treatments outside of bone marrow transplantation Leukocyte adhesion deficiency is a rare genetic disease that prevents inflammatory cells from engaging in the first line of defense against bacterial infectionsRecurrent and refractory infections lead to significant mortality and morbidityeven in moderate casesHills PharmaLLCis developing a novel drug based therapy to directly target the genetic deficiency in this disease